Characterizing the Shared Genetic Underpinnings of Schizophrenia and Cardiovascular Disease Risk Factors

Abstract

Objective: Schizophrenia is associated with increased risk of cardiovascular disease (CVD), although there is variation in risk among individuals. There are indications of shared genetic etiology between schizophrenia and CVD, but the nature of the overlap remains unclear. The aim of this study was to fill this gap in knowledge.

Methods: Overlapping genetic architectures between schizophrenia and CVD risk factors were assessed by analyzing recent genome-wide association study (GWAS) results. The bivariate causal mixture model (MiXeR) was applied to estimate the number of shared variants and the conjunctional false discovery rate (conjFDR) approach was used to pinpoint specific shared loci.

Results: Extensive genetic overlap was found between schizophrenia and CVD risk factors, particularly smoking initiation (N=8.6K variants) and body mass index (BMI) (N=8.1K variants). Several specific shared loci were detected between schizophrenia and BMI (N=304), waist-to-hip ratio (N=193), smoking initiation (N=293), systolic (N=294) and diastolic (N=259) blood pressure, type 2 diabetes (N=147), lipids (N=471), and coronary artery disease (N=35). The schizophrenia risk loci shared with smoking initiation had mainly concordant effect directions, and the risk loci shared with BMI had mainly opposite effect directions. The overlapping loci with lipids, blood pressure, waist-to-hip ratio, type 2 diabetes, and coronary artery disease had mixed effect directions. Functional analyses implicated mapped genes that are expressed in brain tissue and immune cells.

Conclusions: These findings indicate a genetic propensity to smoking and a reduced genetic risk of obesity among individuals with schizophrenia. The bidirectional effects of the shared loci with the other CVD risk factors may imply differences in genetic liability to CVD across schizophrenia subgroups, possibly underlying the variation in CVD comorbidity.

Keywords: Body Mass Index; Cardiovascular Disease; Genetic Overlap; Lifestyle; Schizophrenia Spectrum and Other Psychotic Disorders; Smoking.

FIGURE 1.. Shared and unique polygenic components between schizophrenia and cardiovascular disease phenotypes^a

^a The Venn diagrams illustrate shared and unique trait-influencing variants, showing polygenic overlap (green) between schizophrenia (blue) and cardiovascular disease phenotypes (orange), including A) smoking initiation, B) body mass index (BMI), C) systolic blood pressure (BP), D) diastolic BP, E) type 2 diabetes, and F) high-density lipoprotein (HDL). The numbers in the Venn diagram indicate the estimated quantity of shared and unique trait-influencing variants (in thousands), explaining 90% of single-nucleotide polymorphism heritability in each phenotype, and the standard error. The size of the circles reflects the degree of polygenicity. The genetic correlations (r_g) are also provided. The figures are based on MiXeR analysis.

FIGURE 2.. Common genetic variants jointly associated with schizophrenia and cardiovascular disease phenotypes^a

^a The Manhattan plots show the common genetic variants jointly associated with schizophrenia and A) body mass index (BMI), B) waist-to-hip ratio (adjusted for BMI), C) smoking initiation, D) cigarettes per day, E) triglycerides, F) high-density lipoprotein (HDL), G) low-density lipoprotein (LDL), H) total cholesterol, I) systolic blood pressure (BP), J) diastolic BP, K) type 2 diabetes, and L) coronary artery disease at conjunctional false discovery rate (conjFDR)<0.05. Each panel shows the −log₁₀ transformed conjFDR values for each single-nucleotide polymorphism (SNP) on the y-axis and chromosomal positions along the x-axis. SNPs with conjFDR<0.05 (i.e., −log10 FDR>1.3) are shown with enlarged data points. A black circle around the enlarged data points indicates the most significant SNP in each linkage disequilibrium block. The figure shows the localization of the “conjunctional loci”; additional details are provided in the tables in the online supplement.